EA047200B1 - DOSING A KRAS INHIBITOR FOR THE TREATMENT OF FORMS OF CANCER - Google Patents

Description

Cross references to related applications

This application claims benefit from U.S. Provisional Patent Application No. 62/847,862, filed May 14, 2019, and U.S. Provisional Patent Application No. 62/867,747, filed June 27, 2019, which are incorporated herein by reference in their entirety. to the extent and for all purposes as if fully set forth herein.

State of the art

KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in approximately 25% of patients with NSCLC, and some studies indicate that KRAS mutations are a negative prognostic factor in patients with NSCLC. Recently, mutations in the Kirsten rat sarcoma viral oncogene V-Ki-ras2 homolog (KRAS) homolog were found to confer resistance to epidermal growth factor receptor (EGFR)-targeting therapies in colorectal cancer; accordingly, KRAS mutational status may provide important information before initiating TKI therapy. Taken together, there is a medical need for new ways to treat patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially for those who have been diagnosed with these KRAS-mutated cancers, including those who have progressed after chemotherapy. Oncogenic KRAS mutations at residues G12, G13, and Q61 are the most common RAS mutations found in solid malignancies. Recently, it was demonstrated that KRAS ^G12C can be targeted with covalent small molecule inhibitors that react with a mutant cysteine adjacent to binding pocket II (SIIP), blocking KRAS in its inactive GDP-bound state.

KRAS is the most frequently mutated oncogene in human cancer and encodes a key signaling protein in tumors. The mutant form of KRAS ^G12C contains cysteine, which has been used to create covalent inhibitors with promising preclinical activity. The inventors of the present invention have optimized a series of inhibitors with new binding interactions and have significantly improved the potency and selectivity. These efforts led to the discovery of AMG 510 (also referred to as Compound A herein), the first KRAS ^G12C inhibitor in clinical development. In preclinical studies, treatment with AMG 510 resulted in regression of KRAS p.G12C tumors and significantly improved the antitumor efficacy of chemotherapy and targeted agents. In immunocompetent mice, treatment with AMG 510 resulted in a pro-inflammatory tumor microenvironment and provided long-term cure when combined with immune checkpoint inhibition. Cured mice did not grow isogenic tumors with KRAS p.G12D,4 indicating adaptive immunity against heterologous antigens. AMG 510 demonstrated preliminary evidence of clinical antitumor activity in the first dose-dose cohort and represents a potentially transformative therapy for patients for whom there are no effective treatments.

The KRAS oncoprotein is a GTPase that is an important mediator of intracellular signaling pathways involved in the growth and survival of tumor cells. In normal cells, KRAS functions as a molecular switch that alternates between an inactive GDP-bound and an active GTP-bound state. The transition between these states is facilitated by guanine nucleotide exchange factors (GEFs), which load GTP and activate KRAS, and GTP hydrolysis, which is catalyzed by GTPase-activating proteins (GAPs), to inactivate KRAS. GTP binding to KRAS promotes the binding of effectors that trigger signal transduction pathways involving RAF-MEK-ERK (MAPK). Somatic activating mutations in KRAS are a hallmark of cancer and block GAP association, thereby stabilizing effector binding and enhancing KRAS signaling. Patients with tumors containing a mutant form of KRAS have significantly worse outcomes and prognosis. Although there are clinically approved inhibitors of several MAPK pathway proteins (eg, MEK, BRAF, EGFR) for a subset of tumor types, to date there are no clinical molecules selective for tumors containing a mutant form of KRAS. Moreover, several MAPK pathway-targeted therapeutics are contraindicated for the treatment of KRAS mutant tumors due to lack of clinical efficacy. In addition, non-tumor or mutant-selective therapeutics may cause on-target toxicity due to inhibition of MAPK signaling in normal cells. This may limit the utility of combining such agents with standard treatment or immunotherapy. Thus, there is a critical unmet need to develop tumor-selective therapeutics that do not interfere with normal cells.

KRAS p.G12C is present in approximately 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors. Mutant cysteine residues KRAS ^G12C ,

- 1 047200 adjacent to the pocket (P2), is in the inactive GDP-related form of KRAS. The proximity of P2 and mutant cysteine leads to an extensive search for covalent inhibitors. The first reported electrophilic screen for KRAS ^G12C led to the eventual identification of ARS-1620, which demonstrates in vivo efficacy in preclinical models with KRAS p.G12C. In doing so, Araxes Pharma's ARS-1620 marked a milestone in proof of concept for mutant-selective KRAS inhibition and was positioned as a tool compound for preclinical development. We have identified a series of new acrylamide-based molecules that utilize a previously unexploited groove on the surface of KRAS ^G12C to significantly improve efficiency and selectivity. Intensive electrophilic screening and structure-based design led to the discovery of AMG 510, the first KRAS ^G12C inhibitor to enter clinical testing in humans (see www.clinicaltrials.gov NCT03600883). Herein, the inventors present the compelling clinical efficacy of AMG 510.

Short description

Provided herein are methods of treating cancer comprising administering to a subject in need thereof Compound A at a daily dose of 180 mg, 360 mg, 720 mg or 960 mg. In various cases, the daily dose is 180 mg. In various cases, the daily dose is 360 mg. In various cases, the daily dose is 720 mg. In various cases, the daily dose is 960 mg. The dose can be administered orally. The dose can be administered as a single daily dose. In various cases, the subject is administered Compound A for at least one month, or at least three months, or at least six months.

Subjects to whom the compound is administered in the methods disclosed herein suffer from cancer. The cancer may be a solid tumor. The cancer may be a cancer with the G12C KRAS mutation. In some cases, lung cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer. In various cases, the subject is a person who, prior to initiation of therapy with Compound A, has undergone at least one (eg, at least two) other systemic cancer therapies.

In various cases, a subject administered Compound A for at least a month does not experience any Grade 3 or Grade 4 adverse events associated with therapy with Compound A. In some embodiments, the subject does not experience any Grade 4 adverse events 3 or grade 4 associated with therapy with Compound A after at least three months of administration of Compound A. In various cases, the subject has at least stable disease after administration of Compound A. In some cases, the subject has experienced at least a partial response after introduction of compound A.

In various cases, the methods disclosed herein may include administration of a chemotherapy drug. In some cases, the chemotherapy drug contains an anti-PD1 antibody. In some cases, the anti-PD1 antibody is pembrolizumab (Keytruda), nivolumab, AUNP-12, AMG 404, or pidilizumab. In some cases, the chemotherapy drug contains an antibody to PDL1. In some cases, the anti-PDL1 antibody is atezolizumab, MPDL3280A, avelumab, or durvalumab. In some cases, the chemotherapy drug contains a MEK inhibitor. In which cases, the MEK inhibitor is trametinib, pimasertib, PD-325901, MEK162, TAK-733, GDC-0973, or AZD8330. In some cases, the chemotherapy drug contains a CDK4/6 inhibitor. In some cases, a CDK4/6 inhibitor includes abemaciclib or palbociclib. In some cases, the chemotherapy drug contains a PI3K inhibitor. In some cases, a PI3K inhibitor includes AMG 511 or buparlisib.

Brief description of graphic materials

In the following figures, PD indicates disease progression, PR indicates partial response, and SD indicates stable disease.

In fig. 1 shows the CA 19-9 and CAE biomarker response in a patient with metastatic colon adenocarcinoma administered Compound A at a total daily dose of 360 mg.

In fig. 2 shows tumor responses in the form of non-small cell lung cancer, measured by radiographic studies every six weeks, for nine patients with NSCLC cancer receiving Compound A at various total daily doses, as indicated.

In fig. 3 shows the response and duration of treatment of patients with NSCLC who are administered Compound A at the following total daily doses: top four columns, 960 mg; next six columns - 720 mg; the next column is 360 mg and the bottom three columns are 180 mg.

In fig. 4 shows the responses of colorectal cancer (CRC) and other solid tumors, measured by radiographic examinations every six weeks, for patients with CRC and other solid tumor cancers receiving Compound A at various total daily doses, as indicated.

In fig. 5 shows the response and duration of treatment of patients with CRC and other solid tumors administered Compound A at the following total daily doses: top two columns, 960 mg;

- 2 047200 next five columns - 720 mg; the next eleven columns are 360 mg and the bottom three columns are 180 mg.

In fig. 6 shows the effectiveness of Compound A in patients with NSCLC as a change in tumor weight from baseline. A superscript a in the rightmost column indicates that the patient had a complete response to the target lesion. Superscript b indicates that 1 patient withdrew early from the study due to clinical PD before the 1st assessment with no data available regarding tumor burden after baseline and is therefore not shown in the graph.

In fig. 7 shows the effectiveness of Compound A in patients with NSCLC in terms of response time and duration of treatment. Each bar in the graph, 23 in total, represents a specific patient (N=23) who was administered a specific total daily dose (counting from the top of the graph, Columns 1-3 (180 mg), Column 4 (360 mg), Columns 5-10 (720 mg) and columns 11-23 (960 mg). The superscript a in column 9 indicates that the graph was based on data obtained from the participating study sites at the time data were cut off for the duration of treatment. this patient (column 9) should be removed from the study site.

In fig. Figure 8 shows the possibility of progression-free survival for patients with CRC.

In fig. Figure 9 shows the overall survival potential of patients with CRC.

In fig. Figure 10 shows the change in tumor weight from baseline for patients with CRC.

In fig. 11 shows the change in tumor weight from baseline over time for patients with CRC when administered with all four doses of Compound A (total daily dose of 180 mg, 360 mg, 720 mg and 960 mg).

In fig. 12 shows the change in tumor weight from baseline over time for the subgroup of patients with CRC shown in FIG. 11. In particular, in FIG. 12 shows patients who were administered a dose of Compound A of 180 mg daily.

In fig. 13 shows the change in tumor weight from baseline over time for the subgroup of patients with CRC shown in Figure 11. In particular, FIG. 13 shows patients who were administered a dose of Compound A of 360 mg daily.

In fig. 14 shows the change in tumor weight from baseline over time for the subgroup of patients with CRC shown in Figure 11. In particular, FIG. 14 shows patients who were administered a dose of Compound A of 720 mg daily.

In fig. 15 shows the change in tumor weight from baseline over time for the subgroup of patients with CRC shown in FIG. 11. In particular, in FIG. 15 shows patients who were administered a dose of Compound A of 960 mg daily.

In fig. 16 shows time to response and treatment over time for patients with CRC dosed with Compound A (counting from the top of the graph: bars 1-4 (720 mg), bars 5-14 (360 mg) and bars 15-17 (180 mg).

In fig. 17 shows the time to response and treatment over time for patients with CRC who were administered a dose of Compound A of 960 mg daily.

In fig. 18 shows the effectiveness of Compound A in patients with advanced solid tumors other than NSCLC and CRC, as measured by change in tumor weight from baseline. Superscript a on certain columns indicated that patients had unconfirmed PR. The superscript b on certain three columns designated PR indicates that the patient having appendiceal cancer received 720 mg of the total daily dose of compound A, and the other two patients (having endometrial cancer and melanoma) each received 960 mg of the total daily dose of compound A.

In fig. Figure 19 shows time to response and treatment over time for patients with advanced solid tumors other than NSCLC and CRC.

Detailed description

The present invention provides methods for treating forms of cancer by administration to a co-subject in need thereof. Compound A is characterized by the structure of compound A

. In some cases, Compound A is referred to as AMG 510. Compound A may be present as a pharmaceutically acceptable isotopically labeled version where one or more atoms are replaced by atoms of the same atomic number but an atomic mass or mass number different from the atomic mass or mass number , commonly found in nature. Examples

- 3,047,200 isotopes that may be included in compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus and fluorine, such as ² H, ³ H, C. ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O and ¹⁸ F respectively. These radiolabeled compounds can be used to help determine or measure the potency of Compound A by describing, for example, the site or mechanism of action or binding affinity to a pharmacologically important site of action. Certain radiolabeled versions of Compound A, eg those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. Radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly suitable for this purpose given their ease of administration and ready means for their detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H may provide some therapeutic benefits resulting from greater resistance to inactivation by metabolism, such as increased in vivo half-life or reduced dosage requirements, and is therefore preferred in some circumstances.

Substitution with positron-active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be used in positron emission topography (PET) studies to determine the extent of receptor occupancy by a substrate. Isotopically labeled compounds of structure (I) can generally be prepared using conventional techniques known to those skilled in the art. The isotopically labeled compounds disclosed herein can generally be prepared using conventional techniques known to those skilled in the art.

Compound A can exist as a stereoisomer (ie, isomers that differ only in the spatial arrangement of the atoms), including optical isomers and conformational isomers (or conformers). Compound A referred to herein, unless otherwise indicated, includes all stereoisomers, both as pure preparations of the individual stereoisomers and as fortified preparations of each stereoisomer, and as racemic mixtures of such stereoisomers and individual diastereomers and enantiomers, which may be separated according to methods known to those skilled in the art. In some cases, Compound A is presented as 4(^)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4

methylpyridin-3-yl)pyrido[2.3 N|pyrimidin-2(1H)-one:

Compound A can exist as an atropoisomer, which is a conformational stereoisomer that occurs when rotation around a single bond in a molecule is blocked or greatly slowed down by steric interactions with other parts of the molecule. Compound A referred to herein, unless otherwise indicated, includes all atropisomers, either as pure preparations of the individual atropisomers or fortified preparations of each atropisomer, or a nonspecific mixture of each atropisomer. In cases where the rotational barrier around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species of molecules can be allowed. The separation and isolation of isomeric species of molecules are respectively indicated by the well-known and generally accepted symbols M or P. In some cases, compound A is represented as 4-((b)-4-acryloyl-2methylpiperazin-1 -yl)-6-fluoro-7-( 2-fluoro-6-hydroxyphenyl)-1 -(2-isopropyl-4-methylpyridin-3 yl)pyrido[2,3H|pyrimidin-2(1H)-one and M-atropoisomer

. In some cases, Compound A is presented as 4-(^)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6hydroxyphenyl)-1-(2-isopropyl-4- methylpyridin-3-yl)pyrido[2,3H|pyrimidin-2(1H)-one and M-

atropoisomer

- 4 047200

In some cases, Compound A is presented as 4-(^)-4-acryloyl-2-methylpiperazin-1-yl)6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4 -methylpyridin-3-yl)pyrido[2,3-4]pyrimidin-

2(III)-one and P-atropoisomer. In some cases, Compound A is presented as 4-(U)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl- 4 methylpyridin-3-yl)pyrido[2,3D]pyrimidin-2(1H)-one and P-atropoisomer

. In some cases, the compound is presented as mixtures of the above isomers.

Compound A can be prepared as previously reported, for example as generally disclosed in WO 2018/119183 or more specifically as disclosed in WO 2018/217651.

Compound A can be obtained in the form of a pharmaceutically acceptable salt thereof. Suspected examples of pharmaceutically acceptable salts include base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of the compounds can also be prepared using a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are widely known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. It is also possible to use carbonates or bicarbonates. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium or ferric iron and the like. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N.N'-dibenzylethylenediamine. chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids. Examples of suitable acid addition salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, those formed with formic, acetic, citric, oxalic, tartaric or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phosphonic acids or N-substituted sulfamic acids, for example acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid , tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid and with amino acids such as the 20 alpha amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, as well as with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, or with other acidic organic compounds such as ascorbic acid.

Compound A can be combined with a pharmaceutically acceptable excipient to provide a pharmaceutical composition (also referred to interchangeably as a composition). The excipient may be a diluent or a carrier. Suitable pharmaceutical formulations can be determined by one skilled in the art depending on the route of administration and the required dose. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, PA, USA, 1990). The formulations may affect the physical state, stability, in vivo release rate, and in vivo elimination rate of the administered agents. Depending on the route of administration, the appropriate dose may be calculated according to body weight, body surface area or organ size. Averagely qualified specialists in this field usually

- 5 047200 further refine the calculations necessary to determine the appropriate therapeutic dose without undue experimentation, especially taking into account the dose information and analyzes disclosed herein, as well as the pharmacokinetic data that can be obtained from clinical trials in animals or humans. The phrases pharmaceutically acceptable or pharmacologically acceptable refer to molecular substances and compositions that do not cause adverse, allergic or other adverse reactions when administered to an animal or human. As used herein, the term pharmaceutically acceptable includes all possible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarding agents, and the like. The use of such excipients for pharmaceutically active substances is widely known in the art. Unless any conventional media or agent is incompatible with the therapeutic compositions, their use in the therapeutic compositions is contemplated. Additional active ingredients may also be included in the compositions. In illustrative embodiments, the composition may contain corn syrup powder, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tribasic calcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine , dibasic potassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, chloride sodium, niacinamide, mixed tocopherols, calcium pantothenate, copper(II) sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium trichloride , sodium molybdate, vitamin D3 and cyanocobalamin.

Pharmaceutical compositions containing Compound A can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, trituration, emulsification, encapsulation, entrapment or lyophilization processes. The appropriate formulation depends on the route of administration chosen.

Suitable compositions for oral administration can be readily formulated by combining Compound A with pharmaceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers make it possible to formulate Compound A in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral administration by the patient being treated. Oral medicinal products can be prepared by adding a solid excipient to Compound A, optionally grinding the resulting mixture and processing the mixture into granules after adding suitable excipients to form tablets or dragee cores, if desired. Suitable excipients include, for example, fillers and cellulosic preparations. If required, substances may be added to improve tablet disintegration. Pharmaceutically acceptable ingredients are well known for various types of formulations and may include, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavoring agents, coating materials, preservatives, colorants, thickeners, excipients, antimicrobial agents, antioxidants and carriers for various types of formulations.

When a therapeutically effective amount of Compound A is administered orally, the composition is typically in the form of a solid (eg, tablet, capsule, pill, powder or lozenge) or liquid formulation (eg, aqueous suspension, solution, tincture or syrup). In one embodiment, a therapeutically effective amount of Compound A (eg, 960 mg) is administered orally in the form of a tablet or multiple tablets (eg, 8x120 mg tablets).

When administered in tablet form, the composition may further comprise a functional solid and/or a solid carrier such as gelatin or an excipient. The tablet, capsule and powder may contain from about 1 to about 95% Compound A, and preferably from about 15 to about 90% Compound A.

When administered in the form of a liquid or suspension, a functional liquid and/or a liquid carrier such as water, a hydrocarbon carrier, or oils of animal or plant origin may be added. The liquid form of the composition may further contain saline, solutions of sugar alcohols, solutions of dextrose or other saccharides or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5 to about 90% by weight of Compound A, and preferably from about 1 to about 50% of Compound A. In one embodiment, the liquid carrier is assumed to be non-aqueous or substantially non-aqueous. The composition, intended for administration in liquid form, may be supplied as a rapidly dissolving solid formulation or as a suspension for dissolution immediately prior to administration.

- 6 047200

When a therapeutically effective amount of Compound A is administered by intravenous, dermal, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions having appropriate pH, isotonicity, stability, etc. is within the skill of one skilled in the art. A preferred composition for intravenous, dermal or subcutaneous injection typically contains, in addition to Compound A, an isotonic vehicle. Such compositions can be prepared for administration as solutions of the free base or pharmacologically acceptable salts in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be obtained in glycerin, liquid polyethylene glycols and mixtures thereof, as well as in oils. Under normal conditions of storage and use, such preparations may not necessarily contain a preservative to inhibit the growth of microorganisms.

Injectable compositions may include sterile aqueous solutions, suspensions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions, suspensions or dispersions. In all embodiments, the form must be sterile and must be fluid to the extent that it can be easily syringed. It must be stable under the conditions of manufacture and storage and must resist the contaminating action of microorganisms such as bacteria and fungi through the optional inclusion of a preservative. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one embodiment, the carrier is assumed to be non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, through the use of a coating such as lecithin, through maintaining the desired particle size of the compound in the dispersion embodiment, and through the use of surfactants. Blocking the effects of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomersal, etc. In many embodiments, it will be preferred to include isotonic agents, such as sugars or sodium chloride. Prolonged absorption of injectable compositions can be achieved through the use of absorption retarding agents in the compositions, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating Compound A in the required amount in a suitable solvent with various other ingredients listed above, if necessary, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile carrier medium that contains the basic dispersion medium and the required other ingredients listed above. In the embodiment of sterile powders intended for the preparation of sterile injectable solutions, preferred production methods are vacuum drying and freeze drying techniques that provide a powder of the active ingredient plus any additional required ingredient from a pre-sterile filtered solution thereof.

Slow or sustained release formulations may also be prepared to achieve controlled release of Compound A into contact with body fluids in the gastrointestinal tract and to provide a substantially constant and effective plasma level of the active compound. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Additionally, a slow-release approach may enhance absorption through saturable or limiting pathways in the gastrointestinal tract. For example, for this purpose, the compound may be incorporated into a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both and optionally suitable surfactants. In this context, embedding may mean the incorporation of microparticles into a matrix of polymers. Controlled release formulations are also prepared by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating technologies.

For administration by inhalation, Compound A is delivered in the form of a nebulized aerosol from pressurized packs or by nebulizer using a suitable propellant. In a pressurized aerosol embodiment, a dosage unit may be defined by providing a valve to deliver a metered amount. For use in an inhaler or insufflator, capsules and cartridges, for example gelatin, can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

Compound A can be formulated for parenteral administration by injection (eg, bolus injection or continuous infusion). Injectable formulations may be presented in unit dosage form (eg, ampoules or multi-dose containers) with an added preservative. The compositions may take forms such as suspensions, solutions

- 7 047200 or emulsions in oily or aqueous carrier media, and may contain formulation auxiliaries such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions intended for parenteral administration include aqueous solutions of Compound A in water-soluble form. In addition, the suspensions can be prepared in the form of suitable oily injection suspensions. Suitable lipophilic solvents or carrier media include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of compound A and provide highly concentrated solutions. Alternatively, the composition of the present invention may be in the form of a powder for dilution with a suitable carrier medium (eg, sterile pyrogen-free water) before use.

Compound A may also be formulated into compositions for rectal administration, such as suppositories or retention enemas (eg, containing traditional suppository bases). In addition to the formulations described previously, Compound A can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, Compound A may be formulated using suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt.

In particular, Compound A may be administered orally, buccally or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or vaginal suppositories, either alone or mixed with excipients, or in the form of tinctures or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared using pharmaceutically acceptable additives such as suspending agents. Compound A can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compound is best administered in the form of a sterile aqueous solution, which may contain other substances, such as salts or sugar alcohols such as mannitol or glucose, to render the solution isotonic with blood.

For veterinary use, Compound A is administered in a suitable acceptable formulation in accordance with normal veterinary practice. The veterinarian can easily determine the dosage regimen and route of administration that is most appropriate for a particular animal.

In some embodiments, all of the necessary components for treating a KRAS disorder using Compound A, either alone or in combination with another agent, or for an intervention conventionally used to treat such a disorder, may be packaged in a kit. In particular, the present invention provides a kit for use in a therapeutic intervention for a disease, containing a packaged set of drugs that include Compound A, as well as buffers and other components designed to formulate the delivered forms of said drugs, and/or devices for delivering such medicinal products, and/or any drugs that are used in combination therapy with compound A, and/or instructions for the treatment of the disease contained in the packaging with the medicinal products. The instructions may be recorded on any tangible medium, such as printed paper or computer-readable magnetic or optical media, or the instructions may be provided in the form of a link to a remote computer data source, such as a World Wide Web page accessible via the Internet.

A therapeutically effective amount means an amount effective to treat or prevent the development or amelioration of existing symptoms in the subject being treated. Determination of effective amounts is within the skill of those skilled in the art, especially in light of the detailed disclosure presented herein. Generally, a therapeutically effective dose refers to that amount of Compound A that produces the desired effect. For example, a therapeutically effective amount of Compound A reduces KRAS activity by at least 5% relative to control, at least 10%, at least 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90%.

A therapeutically effective amount means an amount effective to treat or prevent the development or amelioration of existing symptoms in the subject being treated. Determination of effective amounts is within the skill of those skilled in the art, especially in light of the detailed disclosure presented herein. Generally, a therapeutically effective dose refers to that amount of a compound that produces

- 8 047200 to achieve the required effect. For example, in one preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KRAS activity by at least 5% compared to control, by at least 10%, by at least 15%, by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90%.

Although individual needs vary, determination of optimal ranges of effective amounts of a compound is within the skill of those skilled in the art. For administration to humans for the definitive or prophylactic treatment of conditions and disorders identified herein, for example, typical doses of the compounds of the present invention may range from about 0.05 mg/kg/day to about 50 mg/kg/day, for example, at least at least 0.05 mg/kg, at least 0.08 mg/kg, at least 0.1 mg/kg, at least 0.2 mg/kg, at least 0.3 mg/kg, at least at least 0.4 mg/kg or at least 0.5 mg/kg and preferably 50 mg/kg or less, 40 mg/kg or less, 30 mg/kg or less, 20 mg/kg or less or 10 mg/kg kg or less, which may be, for example, from about 2.5 mg/day (0.5 mg/kg x 5 kg) to about 5000 mg/day (50 mg/kg x 100 kg). For example, dosages of the compounds may range from about 0.1 mg/kg/day to about 50 mg/kg/day, from about 0.05 mg/kg/day to about 10 mg/kg/day, from about 0.05 mg /kg/day to about 5 mg/kg/day, from about 0.05 mg/kg/day to about 3 mg/kg/day, from about 0.07 mg/kg/day to about 3 mg/kg/day , from about 0.09 mg/kg/day to about 3 mg/kg/day, from about 0.05 mg/kg/day to about 0.1 mg/kg/day, from about 0.1 mg/kg/day day to about 1 mg/kg/day, from about 1 mg/kg/day to about 10 mg/kg/day, from about 1 mg/kg/day to about 5 mg/kg/day, from about 1 mg/kg /day to about 3 mg/kg/day, from about 1 mg/day to about 960 mg/day, from about 20 mg/day to about 720 mg/day, from about 3 mg/day to about 500 mg/day, from about 5 mg/day to about 360 mg/day, from about 10 mg/day to about 100 mg/day, from about 3 mg/day to about 10 mg/day, from about 100 mg/day to about 250 mg/day day. Such doses may be administered in a single dose or they may be divided into several doses.

In certain embodiments, Compound A is administered to a subject in need thereof orally and once daily. In some cases, the subject is administered a total daily amount of 180 mg, 360 mg, 720 mg, or 960 mg. In some cases, the total daily amount of Compound A administered is 180 mg. In some cases, the total daily amount of Compound A administered is 360 mg. In some cases, the total daily amount of Compound A administered is 720 mg. In some cases, the total daily amount of Compound A administered is 960 mg. In some cases, Compound A is administered in divided daily doses, such as two, three, four, five or six times per day.

Embodiments

In a first embodiment, the present invention provides a method of treating cancer comprising administering to a subject in need thereof Compound A at a daily dose of 180 mg, 360 mg, 720 mg or 960 mg, wherein Compound A has the following structure:

In the 2nd embodiment ^, the present invention provides a method according to ^embodiment 1, wherein compound A has the structure m—'.

In the 3rd embodiment, the present invention provides a method according to the embodiment

- 9 047200

Μ'

implementation 1, where compound A is characterized by structure .

In the 4th embodiment, the present invention provides a method according to any of embodiments 1, 2 or 3, wherein the cancer is a solid tumor.

In the 5th embodiment, the present invention provides a method according to any of embodiments 1, 2, 3 or 4, wherein the cancer is non-small cell lung cancer.

In the 6th embodiment, the present invention provides a method according to any of embodiments 1 to 4, wherein the cancer is colorectal cancer.

In the 7th embodiment, the present invention provides a method according to any of embodiments 1 to 4, wherein the cancer is pancreatic cancer.

In the 8th embodiment, the present invention provides a method according to any one of embodiments 1 to 7, wherein the cancer is a cancer with the G12C KRAS mutation.

In the 9th embodiment, the present invention provides a method according to any of embodiments 1-8, wherein the subject has undergone at least one other systemic cancer therapy prior to initiation of therapy with Compound A.

In the 10th embodiment, the present invention provides a method according to embodiment 9, where the subject has undergone at least two other types of systemic cancer therapy.

In the 11th embodiment, the present invention provides a method according to any of embodiments 1 to 9, wherein Compound A is administered orally.

In the 12th embodiment, the present invention provides a method according to any of embodiments 1 to 11, wherein Compound A is administered as a single daily dose.

In a 13th embodiment, the present invention provides a method according to any of embodiments 1-12, wherein the subject does not experience any Grade 3 or Grade 4 adverse events associated with therapy with Compound A after administration of Compound A for at least 1 month.

In a 14th embodiment, the present invention provides a method according to embodiment 13, wherein the subject does not experience any Grade 3 or Grade 4 adverse events associated with therapy with Compound A after administration of Compound A for at least 3 months.

In the 15th embodiment, the present invention provides a method according to any of embodiments 1 to 14, wherein the dose of Compound A is 180 mg.

In the 16th embodiment, the present invention provides a method according to any of embodiments 1 to 14, wherein the dose of Compound A is 360 mg.

In the 17th embodiment, the present invention provides a method according to any of embodiments 1 to 14, wherein the dose of Compound A is 720 mg.

In the 18th embodiment, the present invention provides a method according to any of embodiments 1 to 14, wherein the dose of Compound A is 960 mg.

In the 19th embodiment, the present invention provides a method according to any of embodiments 1-18, wherein the subject is administered Compound A for at least one month.

In the 20th embodiment, the present invention provides a method according to any of embodiments 1-18, wherein the subject is administered Compound A for at least three months.

In the 21st embodiment, the present invention provides a method according to any of embodiments 1-18, wherein the subject is administered Compound A for at least six months.

In the 22nd embodiment, the present invention provides a method according to any of embodiments 19-21, wherein the subject has at least a stable disease (SD).

In the 23rd embodiment, the present invention provides a method according to embodiment 22, wherein the subject exhibits at least a partial response (PR).

In a 24th embodiment, the present invention provides a method according to any of embodiments 1-23 wherein the subject does not experience dose-limiting toxicity (DLT).

In the 25th embodiment, the present invention provides a method according to any of embodiments 1-24, wherein compound A is an M-atropisomer.

In the 26th embodiment, the present invention provides a method according to any of embodiments 1-25, further comprising administering a chemotherapeutic agent to the subject.

- 10 047200 Russian drug.

In the 27th embodiment, the present invention provides a method according to embodiment 24, wherein the chemotherapy drug contains an anti-PD1 antibody.

In the 28th embodiment, the present invention provides a method according to embodiment 25, wherein the anti-PD1 antibody is pembrolizumab (Keytruda), nivolumab, AUNP12, AMG 404 or pidilizumab.

In the 29th embodiment, the present invention provides a method according to embodiment 26, wherein the chemotherapy drug contains an anti-PDL1 antibody.

In the 30th embodiment, the present invention provides a method according to embodiment 29, wherein the anti-PDL1 antibody is atezolizumab, MPDL3280A, avelumab or durvalumab.

In Embodiment 31, the present invention provides a method according to Embodiment 26, wherein the chemotherapy drug contains an anti-MEK antibody.

In the 32nd embodiment, the present invention provides a method according to embodiment 31, wherein the MEK inhibitor is trametinib, pimasertib, PD-325901, MEK162, TAK-733, GDC-0973 or AZD8330.

In the 33rd embodiment, the present invention provides a method according to embodiment 26, wherein the chemotherapy drug contains an anti-CDK4/6 antibody.

In Embodiment 34, the present invention provides a method according to Embodiment 33, wherein the CDK4/6 inhibitor comprises abemaciclib or palbociclib.

In the 35th embodiment, the present invention provides a method according to embodiment 26, wherein the chemotherapy drug contains a PI3K inhibitor.

In the 36th embodiment, the present invention provides a method according to embodiment 35, wherein the PI3K inhibitor comprises AMG 511 or buparlisib.

In the 37th embodiment, the present invention provides a method according to embodiment 22, where the stable disease is neither a sufficient proportional decrease in size to be defined in relation to PR, nor a sufficient increase to be defined in relation to PD.

In the 38th embodiment, the present invention provides a method according to embodiment 23, where the partial response is a reduction of at least 30% in the sum of the diameters of the target lesions.

In an alternative first embodiment, the present invention provides Compound A at a daily dosage of 180 mg, 360 mg, 720 mg, or 960 mg for the treatment of cancer, wherein Compound A has the following structure:

In another alternative first embodiment, the present invention provides for the use of Compound A at a daily dose of 180 mg, 360 mg, 720 mg or 960 mg in the preparation of a medicinal product, wherein Compound A has the following structure:

Methods of using compound A.

In embodiments of the methods disclosed herein, the subject is administered Compound A at the disclosed dosage for at least one month, at least six weeks, at least two months, at least three months, at least four months, at least five months or at least six months.

In some embodiments of the methods disclosed herein, the subject is administered Compound A at a disclosed dosage orally at least once daily (QD).

In some embodiments of the methods disclosed herein, the subject is administered Compound A at a disclosed dosage orally at least twice daily (BID).

The present invention provides a method of inhibiting RAS-mediated cell signaling, comprising contacting the cell with an effective amount of Compound A.

- 11 047200

Inhibition of RAS-mediated signal transduction can be assessed and demonstrated using a wide variety of pathways known in the art. Non-limiting examples include demonstrating (a) a decrease in GTPase activity of RAS; (b) decreasing the binding affinity of GTP or increasing the binding affinity of GDP; (c) increasing K _off GTP or decreasing K _off GDP; (d) reducing the levels of signal transduction molecules located downstream in the RAS pathway, for example, reducing the levels of pMEK, pERK or pAKT; and/or (e) reducing the extent of binding of the RAS complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be used to determine one or more of the above.

The present invention also provides methods of using Compound A or the pharmaceutical compositions of the present invention to treat disease states, including, but not limited to, conditions associated with the G12C KRAS, HRAS, or NRAS mutation (eg, cancer).

In some embodiments, a method of treating cancer is provided, the method comprising administering to a subject in need thereof an effective amount of Compound A disclosed herein. In some embodiments, the cancer is mediated by the G12C mutation of KRAS, HRAS, or NRAS. In various embodiments, the cancer is pancreatic cancer, colorectal cancer, or lung cancer (eg, non-small cell lung cancer (locally advanced or metastatic)). In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and bile duct cancer.

In some embodiments, the present invention provides a method of treating a disorder in a subject in need thereof, wherein the method includes determining whether the subject has a G12C KRAS, HRAS, or NRAS mutation, and if the subject is determined to have a G12C KRAS, HRAS, or NRAS mutation then administering to the subject a therapeutically effective dose of Compound A or a pharmaceutically acceptable salt thereof.

The disclosed compounds inhibit anchorage protein-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another embodiment, the present invention provides a method of inhibiting tumor metastasis, the method comprising administering an effective amount of Compound A.

G12C KRAS, HRAS, or NRAS mutations have also been identified in hematologic malignancies (eg, forms of cancer that involve the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments are directed to administering Compound A (eg, in the form of a pharmaceutical composition) to a patient in need of treatment for hematologic malignancy. Such cancers include, but are not limited to, leukemias and lymphomas. For example, Compound A can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia ( AMoL) and/or other types of leukemia. In other embodiments, Compound A is useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, Compound A is useful for the treatment of plasma cell malignancies, such as multiple myeloma, mantle cell lymphoma, and Waldenström's macroglobulinemia.

Determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can be made by assessing the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein, by assessing the amino acid sequence of the KRAS, HRAS, or NRAS protein, or by assessing the characteristics of a putative mutant KRAS protein , HRAS or NRAS. The sequence of wild type human KRAS, HRAS or NRAS is known in the art (eg accession no. NP203524).

Methods for detecting mutations in a KRAS, HRAS, or NRAS nucleotide sequence are known to those skilled in the art. Such methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) assays, and PCR-mode assays. real-time, sequencing of PCR products, assays using mutant allele specific PCR amplification (MASA), direct sequencing, primer extension reactions, electrophoresis, oligonucleotide probe ligation, hybridization assays, TaqMan assays, SNP genotyping, melting assays high-resolution and microarray analyses. In some embodiments, samples are assessed for G12C KRAS, HRAS, or NRAS mutations using real-time PCR. Real-time PCR uses fluorescent probes specific for the G12C KRAS, HRAS, or NRAS mutations. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the G12C mutation of KRAS, HRAS, or NRAS is identified using a method of direct sequencing of specific regions (eg, exon 2 and/or exon 3) in the KRAS, HRAS, or NRAS gene. This technique will allow us to identify all possible mutations in the sequence

- 12 047200 bathroom area.

Methods for detecting mutations in a KRAS, HRAS, or NRAS protein are known to those skilled in the art. Such methods include, but are not limited to, detection of mutant KRAS, HRAS or NRAS using a binding agent (eg, antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

Methods for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation may use a number of samples. In some embodiments, the sample is collected from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

The present invention also provides a method of treating a hyperproliferative disorder in a mammal, which comprises administering to said mammal a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to treating a subject who is suffering from cancer, such as acute myeloid leukemia, adolescent cancer, childhood adrenal carcinoma, AIDS-related cancers (eg, lymphoma and Kaposi's sarcoma), anal cancer , appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid , embryonal tumors, embryonal cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer , craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germinal cell tumor, extragonadal germinal cell tumor, cancer eyes, fibrous histiocytoma of bone, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germinal cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck with occult primary disease, midline carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasia, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasias, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histio bone cytoma and osteosarcoma , nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus cancer and nasal cavity, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer , stomach cancer (GIT), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymus carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, unusual childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disorder, such as benign cutaneous hyperplasia (eg, psoriasis), restenosis, or a prostate-related disorder (eg, benign prostatic hypertrophy (BPH)).

In some embodiments, the treatment methods are directed to treating forms of lung cancer, the methods comprising administering an effective amount of Compound A (or a pharmaceutical composition containing it) to a subject in need thereof. In some embodiments, the lung cancer is non-small cell lung carcinoma (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the lung cancer is small cell lung carcinoma. Other forms of lung cancer that can be treated with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.

- 13 047200

The present invention further provides methods for modulating the activity of an O12C mutant KRAS, HRAS, or NRAS protein by contacting the protein with an effective amount of Compound A. The modulation may inhibit or activate the activity of the protein. In some embodiments, the present invention provides methods for inhibiting protein activity by contacting a G12C mutant KRAS, HRAS, or NRAS protein with an effective amount of Compound A in solution. In some embodiments, the present invention provides methods for inhibiting the activity of a G12C mutant KRAS, HRAS, or NRAS protein by bringing a cell, tissue, or organ that expresses the protein of interest into contact. In some embodiments, the present invention provides methods for inhibiting protein activity in a subject, including but not limited to rodents and mammals (eg, humans), by administering to the subject an effective amount of Compound A. In some embodiments, the percentage of modulation is greater than 25%, 30% , 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in a cell by contacting said cell with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in the cell. In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in a tissue by contacting said tissue with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in the tissue. In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in an organism by contacting the organism with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in the organism. In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in an animal by contacting said animal with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in said animal. In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in a mammal by contacting said mammal with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in said mammal. In some embodiments, the present invention provides methods for inhibiting G12C KRAS, HRAS, or NRAS activity in a human by contacting the human with an amount of Compound A sufficient to inhibit G12C KRAS, HRAS, or NRAS activity in the human. The present invention provides methods for treating a disease mediated by G12C KRAS, HRAS or NRAS activity in a subject in need of such treatment.

Subject selection and therapeutic outcomes.

In some embodiments, the subject treated with Compound A in the disclosed methods is a subject who has undergone at least one or more prior systemic cancer therapies (eg, Compound A represents a second or third line of therapy). In some embodiments, the subject treated with Compound A in the disclosed methods is a subject who has disease progression following at least one previous systemic cancer therapy (ie, Compound A represents a second line of therapy). In some embodiments, the subject treated with Compound A in the disclosed methods is a subject who has disease progression after at least two prior systemic cancer therapies (ie, Compound A represents a third line of therapy). Previous systemic cancer therapies can be any therapy approved by a regulatory agency (eg, FDA or EMA) as a treatment for a given cancer type and stage. In some cases, the previous systemic cancer therapy is a cancer therapy that has not yet been approved by a regulatory agency but is undergoing clinical trials. If the subject has been exposed to previous systemic cancer therapy, then in some cases the subject has not been exposed to any systemic cancer therapy for at least two months, at least three months, at least four months, at least five months, or at least six months prior to initiation of therapy disclosed herein with Compound A.

In some embodiments, the subject will have a diagnostically confirmed pathological, locally advanced, or metastatic malignancy with a p mutation. G12C KRAS determined by molecular testing. The mutation will be confirmed through central laboratory testing prior to inclusion.

In some embodiments, for NSCLC, subjects could receive platinum-containing combination therapies and/or targeted therapies (i.e., if molecular testing

- 14 047200 identified mutations in EGFR, ALK or the ROS proto-oncogene [ROS1], encoding protein kinase, or the expression of programmed death protein ligand [PD-L1]) before obtaining AMG 510 (compound A).

In some embodiments, the subjects' NSCLC must have progressed after receiving immunotherapy using an anti-PD1 or PD-L1 antibody (unless contraindicated) and/or combination therapy with platinum-containing agents and targeted therapy (if active oncogenic driver [i.e., EGFR] mutations were identified , ALK and ROS1]). Subjects must have received no more than 3 previous lines of therapy.

In some embodiments, for colorectal cancer (CRC), subjects must have received at least 2 previous systemic regimens when treating metastatic cancer. For those CRC subjects with tumors that are MSI-H, at least 1 of the previous systemic regimens must have been treatment with either nivolumab or pembrolizumab if they were clinically able to take inhibitors and 1 of these agents is approved for this indication in a region or country.

In some embodiments, the subjects' CRC must have progressed after receiving fluoropyrimidine and oxaliplatin and irinotecan. For those CRC subjects with tumors that are MSI-H, at least 1 of the previous systemic regimens must include anti-PD1 antibody therapy if they were clinically able to take inhibitors and 1 of these agents is approved for this indication in the region or country.

In some embodiments, for advanced solid tumor types other than NSCLC or CRC, subjects must have received at least one prior systemic therapy to be intolerant or ineligible for available therapies known to provide clinical benefit.

In some embodiments, doses of Compound A may optionally be administered to the subject with food, such as consuming a standardized high-calorie, high-fat meal or in a fasted state (no food or liquid except water for >10 hours). In one embodiment, a dose of Compound A (eg, 960 mg once daily) is administered with or without food.

The subject undergoing therapy is monitored for adverse events (AEs) throughout the course of therapy. A treatment-associated AE is an AE that is associated with a drug. A treatment-emergent AE is an AE that develops in a subject being treated that was not present before the start of therapy. In some cases, treatment-emergent AEs are unrelated or presumably unrelated to the treatment itself. AEs are characterized by one of five grades: grade 1 represents mild AE; grade 2 represents moderate AE; grade 3 represents severe AE; grade 4 represents life-threatening or disabling AE; and grade 5 represents AE-related death. In some cases, the subject does not experience any grade 3 AE that is related to treatment. In some cases, the subject does not experience any Grade 3 AE. In some cases, the subject does not experience any Grade 4 AE that is treatment related. In some cases, the subject does not experience any grade 4 AE. In various cases, the subject does not experience any grade 3 or grade 4 treatment-related AE after administration of Compound A for at least one month or at least three months .

In various cases, a subject treated with Compound A in the methods disclosed herein does not experience any dose-limiting toxicity (DLT) at the dose administered. A DLT is any AE meeting the criteria listed below occurring during the first cycle of treatment with Compound A (Day 1 to Day 21) where a drug interaction cannot be excluded. AE grading is based on the recommendations provided in CTCAE version 5.0. AE for DLT assessment.

Hematological toxicity: febrile neutropenia; infection with neutropenia; neutropenia grade 4; thrombocytopenia grade >3 for >7 days; thrombocytopenia grade 3 with bleeding grade >2; thrombocytopenia grade 4; anemia grade 4.

Nonhematologic toxicity grade >4, vomiting or diarrhea; grade 3 diarrhea or grade 3 vomiting lasting more than 3 days despite optimal medical support; grade 3 nausea for 3 days or more despite optimal medical support; AE any other degree >3.

In various cases, a subject according to the disclosed methods will respond to therapy. In some cases, the subject exhibits at least stable disease (SD) due to administration of Compound A. In some cases, the subject demonstrates at least a partial response (PR) due to administration of Compound A. The subject's response is assessed according to the criteria defined by RECIST 1.1, e.g. discussed in Eisenhauer et al., Eur J Cancer, 45:228–247 (2009). Complete response (CR) is the disappearance of all target lesions and any abnormal lymphatic

- 15 047200 units are characterized by a reduction in the short axis to less than 10 mm. Partial response (PR) represents a reduction of at least 30% in the sum of target lesion diameters, using the baseline sum of diameters as the reference. Disease progression is an increase of at least 20% in the sum of target lesion diameters, using the smallest sum in the study as reference (including baseline if it is the smallest in the study), and there must be an absolute increase of at least 5 mm in addition to a relative increase of 20%. Stable disease represents neither a sufficient proportional decrease in size to be defined as PR nor a sufficient increase to be defined as PD. Controlled disease occurs when a patient can alternate between stable disease and a partial response. The size of the tumor can be measured using radiographic examination.

Combination therapy.

The present invention also provides methods for implementing combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, is used in combination with Compound A or a pharmaceutically acceptable salt thereof. . In one aspect, such therapy includes, without limitation, combining Compound A disclosed herein with a chemotherapeutic agent to provide a synergistic or additive therapeutic effect.

There are many chemotherapeutic drugs currently known in the art and may be used in combination with Compound A. In some embodiments, the chemotherapeutic drug is selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cell inhibitors cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), Venclexta™ (venetoclax) and Adriamycin™ (docorubicin), as well as a chemotherapeutic agent carrier. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan™); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylene imines and methyl melamines, including altretamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphoramide and trimethylol melamine; nitrogen mustards, such as chlorambucil, chlornaphasine, chlorocyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorzotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheycin, carabicin, carminomycin, carcinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6diazo-5-oxo-b-norleucine, doxorubicin, epirubicin, bicine , idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, cinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6mercaptopurine, thiamiprin, thioguanine; pyrimidine analogues such as antsitabine, azacitidine, 6azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepithiostane, testolactone; inhibitors of adrenal hormone synthesis, such as aminoglutethimide, mitotane, trilostane; folic acid compensators such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquon; elfomitin; elliptinium acetate; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamole; nitracrine; pentostatin; phenomet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sisofiran; spirogermanium; tenuazonic acid; triaziquon; 2,2',2-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustin; mitobronitol; mitolactol; pipobromance; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, such as paclitaxel and docetaxel; retinoic acid; esperamycins; capecitabine and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Also included as suitable cell-enhancing chemotherapeutic agents are antihormonal agents that act to regulate or inhibit the action of hormones on tumors, such as antiestrogens, including, for example, tamoxifen, (Nolvadex™), raloxifene, aromatase inhibitors 4(5 )-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); as well as antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; meh

- 16 047200 totrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; Novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO).

Compound A can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, Avicin, Abagovomab, Acridine carboxamide, Adecatumumab, 17-Y -allylamino-17demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, CD22 immunotoxins, antitumor, antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, non-specific cell cycle antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocytabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, Imexon , imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw extract, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38 , salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporphine, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatinum tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

Compound A is contemplated for use in co-therapy with a chemotherapeutic drug that is an antineoplastic agent, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, Arglabin, a mouse trioxide, you 002 (novelos), bexarot, bikalumide, Broxuridin, Capecitabin, Celmolekin, Cetrollix, Komnianbin, Cutroimazole, Citarabin Okfosfate, DA 3030 (Dong-A), Denilekin Diftitox, Dexoroversen, Dexorovsan Lazep, Docatoxel , docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT-diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, ulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamycin, gimeracil/oteracil/tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human germline alpha-fetoprotein, ibandronic acid, idarubicin, ( imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-Nl, interferon alpha- _||3 . interferon alphacon-1, interferon-alpha, natural interferon-beta, interferon-beta-1a, interferon beta-1b, interferon-gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, yobenguan, irinotecan, irsogladin , lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, mazoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, ostim, non-complementary double-stranded RNA , mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, new erythropoiesis-stimulating protein, octreotide NSC 631570, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, gas, peginterferon-alpha 2b, sodium pentosan polysulfate, pentostatin, picibanil, pyrarubicin, rabbit antithymocyte polyclonal antibodies, polyethylene glycol interferon-alpha-2a, sodium porfimer, raloxifene, raltitrexed, razburicase, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sisofiran, sobuzoxan, sonermine, strontium-89 chloride, suramin, tazonermine, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlordecoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomabyod 131, , treosulfan, tretinoin , trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulysin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aetema), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquon, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, halocitabine, gastrin 17 immunogen, HLA-B7 for gene therapy (Vical), granulocyte macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifen, LDI 200 (Milkhaus), leridistim, lintuzumab, MAb CA 125 (Biomira), anticancer MAb (Japan Pharmaceutical Development), MAb HER-2 and Fc (Medarex), idiotypic MAb 105AD7 (CRC Technology), idiotypic MAb CEA (Trilex), MAb LYM-1-iodine 131 (Techniclone), Yttrium 90-labeled polymorphic epithelial mucin MAb (Antisoma), marimastat, menogaryl, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P

- 17 047200

30, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL 172 (SR Pharma), SU 5416 (SuGeN), TA 077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopoietin , ethylethiopurpurine stannous, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (NYU), melanoma vaccine (Sloan-Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital) or valspodar.

Compound A can be used in combination with a chemotherapeutic drug that is a PD1 inhibitor, a PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, or a CDK4/6 inhibitor.

The ^G12C KRAS inhibitors of the present invention can be used in combination with MEK inhibitors. Specific MEK inhibitors that can be used in the combinations of the present invention include PD-325901, trametinib, pimasertib, MEK162 [also known as binimetinib], TAK-733, GDC-0973 and AZD8330. A particular MEK inhibitor that can be used together with a ^G12C KRAS inhibitor in the combinations of the present invention is trametinib (brand name: Mekinist®, commercially available from Novartis Pharmaceuticals Corp.). Another specific MEK inhibitor is N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2fluoro-4-iodophenyl)amino)benzamide, also known as AMG 1009089, 1009089 or PD-325901. Another specific MEK inhibitor that can be used in the combinations of the present invention includes cobimetinib. In some cases, the MEK inhibitor is CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, or PD-325901.

In another aspect, Compound A can be used in combination with one or more agents that are an inhibitor of a protein in the phosphatidylinositol 3-kinase (PI3K) pathway. Examples of proteins in the PI3K pathway include PI3K, mTOR, and PKB (also known as Akt or AKT). The PI3K protein exists in several isoforms, including α, β, δ, or γ. It is expected that a PI3K inhibitor may be selective for one or more isoforms. By selective is meant that the compounds inhibit one or more isoforms to a greater extent than other isoforms. Selectivity is a concept well known to those skilled in the art and can be measured using well known in vitro or cell-based activity assays. Preferred selectivity includes selectivity that is greater than 2-fold, preferably 10-fold, or more preferably 100-fold greater for one or more isoforms than for other isoforms. In one aspect, PI3K inhibitors that can be used in combination with Compound A are selective PI3K α inhibitors. In another aspect, the compound is a selective PI3Kδ inhibitor. In yet another aspect, the compound is a selective PI3K β inhibitor.

Examples of PI3K inhibitors that can be used in combination with Compound A include those disclosed in the following documents: PCT Published Application No. WO 2010/151791; published application according to PCT No. WO 2010/151737; published application according to PCT No. WO 2010/151735; published application under PCT No. WO 2010151740; published application according to PCT No. WO 2008/118455; published application according to PCT No. WO 2008/118454; published application according to PCT No. WO 2008/118468; US Patent Application Published No. US 20100331293; Published US Patent Application No. US 20100331306; US Patent Application Published No. US 20090023761; US Patent Application Published No. US 20090030002; US Patent Application Published No. US 20090137581; US Patent Application Published No. US2009/0054405; US Patent Application Published No. US2009/0163489; US Patent Application Published No. US2010/0273764; Published US Patent Application No. US 2011/0092504 or Published PCT Application No. WO 2010/108074.

In particular, PI3K inhibitors include, but are not limited to, wortmannin, the 17hydroxy wortmannin analogues described in WO 06/044453, 4-[2-(III-indazol-4-yl)-6-[[4(methylsulfonyl)piperazin-1-yl]methyl ]thieno[3,2^]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT publication nos. WO 09/036082 and WO 09/055730), 2-methyl-2-[4-[ 3methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]npropionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in publication according to PCT No. WO 06/122806), (S)-1(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2^]pyrimidin-6- yl)methyl)piperazin-1yl)-2-hydroxypropan-1-one (described in publication according to PCT No. WO 2008/070740), LY294002 (2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one , available from Axon Medchem), PI 103 hydrochloride (3-[4(4-morpholinylpyrido-[3',2':4,5]furo[3,2^]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5nitrobenzenesulfonohydrazide hydrochloride, available from Axon Medchem), PIK 90 (N(7,8-dimethoxy2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Axon Medchem), GDC-0941 bismesylate (2-(N-indazol-4-yl )-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2- 18 047200

d]pyrimidine bismesylate, available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)furan-2-yl]-meth-(2)-ylidene]-thiazolidin-2 ,4-dione, available from Axon Medchem) and TGX-221 (7-methyl-2(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin- 4-on, available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, palomide 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG 100-115, CAL263, PI-103 , GNE-477, CUDC-907 and AEZS136.

Preferred PI3K inhibitors for use in combination with a compound of the present invention include

, also known as buparlisib, an investigational small molecule from Novartis

pharmaceuticals,

; or ; or a pharmaceutically acceptable salt thereof.

Also preferred as a PI3K inhibitor are a compound of formula IIa below or

X ¹ Y ¹ Z ¹

a pharmaceutically acceptable salt thereof, ^a , where X ¹ represents fluorine or hydrogen; Y ¹ represents hydrogen or methyl; and Z ¹ represents hydrogen or methyl. A particular PI3K inhibitor that can be used in combinations is AMG 511 (also known as AMG 2539965 or 2539965), which is presented in Example 148 of published PCT application WO 2010/126895.

Other PI3K inhibitors that can be used in combination with Compound A in the combinations disclosed herein include inhibitors of all types of PI3K, such as BKM120 and GDC0941; selective PI3Ka inhibitors such as AMG 511 and BYL719; and selective PI3K β inhibitors such as GSK-2636771.

Compounds are known that inhibit both PI3K and mTOR (dual inhibitors). In yet another aspect, the present invention provides for the use of dual PI3K and mTOR inhibitors for use in combination with ^G12C KRAS inhibitors. An example of a specific dual inhibitor is GDC-0980.

mTOR is a protein in the PI3K pathway. Another aspect of the present invention is the use of an mTOR inhibitor in combination with ^G12C KRAS inhibitors. mTOR inhibitors that can be used in combination with Compound A include those disclosed in PCT Published Application No. WO 2010/132598 and PCT Published Application No. WO 2010/096314. mTOR inhibitors that can be used in combination with Compound A include AZD2014 and MLN0128.

PKB (AKT) is also a protein in the PI3K pathway. Another aspect of the present invention is

- 19 047200 use of an AKT inhibitor in combination with compound A. AKT inhibitors that can be used include those disclosed in the following documents: US patent No. 7354944; US Patent No. 7700636; US Patent No. 7919514; US patent No. 7514566; publication of US patent application No. US 2009/0270445 A1; US patent No. 7919504; US patent No. 7897619 or published application according to PCT No. WO 2010/083246 A1. Specific AKT inhibitors that can be used in combinations include MK-2206, GDC-0068 and AZD5363.

Compound A can also be used in combination with CDK4 and/or 6 inhibitors. CDK 4 and/or 6 inhibitors that can be used in the combinations of the present invention include, but are not limited to, those disclosed in: PCT Published Application No. WO 2009/085185 or publication of US patent application No. US 2011/0097305.

Anti-PD-1 antibodies include, but are not limited to, pembrolizumab (Keytruda™), nivolumab, AUNP-12, AMG401, and pidilizumab. Exemplary anti-PD-1 antibodies and methods of their use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757–1761 (2007) and Korman et al. in International Application No. PCT/JP2006/309606 (Publication No. WO 2006/121168 A1), each of which is expressly incorporated herein by reference.

Compound A may be used in combination with the agents disclosed herein or other suitable agents depending on the condition being treated. Therefore, in some embodiments, Compound A will be administered in conjunction with other agents described above. When used in combination therapy, Compound A is administered simultaneously or separately with the second agent. This combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, Compound A and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, Compound A and any of the agents described above can be administered simultaneously, where both agents are present in separate formulations. In another alternative, administration of Compound A may be immediately followed by administration of any of the agents described above, or vice versa. In some embodiments of a separate administration protocol, Compound A and any of the agents described above are administered several minutes apart, or several hours apart, or several days apart.

Examples

Phase 1 study of Compound A.

First results.

Compound A dosing study: The study included patients identified as having cancer with the G12C KRAS mutation. Patients were adult patients with locally advanced or metastatic solid tumors with the G12C KRAS mutation. All patients had previously received previous standard therapies depending on tumor type and disease stage. No patients had active brain metastases. Patients in the dosing study had the following diagnoses: 14 with non-small cell lung cancer (NSCLC); 10 with colorectal cancer (CRC) and two with other solid tumors with the G12C KRAS mutation. Compound A was administered orally once a day at the calculated dose. Patients were given doses of Compound A of 180 mg, 360 mg, 720 mg or 960 mg and underwent radiographic examinations every six weeks.

Adverse events observed when taking Compound A are shown in Table. 1 and 2 below. Of the six serious adverse events observed, none were observed to be related to Compound A. Of the six serious adverse events, two were grade 3 (1 pneumonia, 1 malignant biliary obstruction); one grade 4 (pericardial effusion) and three fatal (1 dyspnea and 2 metastatic colorectal cancer). No patients experienced any DLTs, associated grade 4 adverse events, or serious associated adverse events.

- 20 047200

Table 1

Adverse event that occurred during treatment

Adverse event Art. 1 η Art. 2 η St.Z η All powers of η Any unwanted phenomenon that occurred during treatment 25 Decreased appetite 3 3 0 6 Diarrhea 5 0 1 6 Fatigue 1 3 1 5 Headache 3 1 1 5 Cough 2 2 0 4 Hot flush 4 0 0 4 Nausea 4 0 0 4

table 2

- 21 047200 ^a Patient had grade 2 anemia at baseline;

^b lasting 2 days.

Individual Response to Compound A Therapy: Case #1 is a 61 year old woman diagnosed with metastatic NSCLC with G12C KRAS in 2010 and had received prior carboplatin/Taxol therapy from August 2010 to October 2010; then carboplatin/pemetrexed from October 2016 to June 2017; then nivolumab from August 2017 to April 2018; then Compound A was administered at a dose of 180 mg. She had a partial response at 180 mg (-34%) at one of her six-week assessments. She tolerated the drug and continued its administration for more than 27 weeks.

Case #2 is a 59-year-old man diagnosed with metastatic NSCLC with G12C KRAS in 2013 and had received prior carboplatin/pemetrexed therapy from February 2014 to February 2015; erlotinib from April 2015 to June 2015; nivolumab from August 2015 to August 2017; dasatinib from July 2016 to August 2017; M3541 (targeted biologicals) from October 2017 to November 2017; then Compound A was administered at a dose of 360 mg. He had a partial response (-80%) at one of his six-week assessments. He tolerated the drug and continued its administration for more than 14 weeks.

Case #3 is a 34 year old woman diagnosed with metastatic colon adenocarcinoma with G12C KRAS in 2014 and received prior therapy with FOLFOX and HIPEC in August 2015 followed by FOLOX until December 2015; FOLFIRI with PD in August 2016; HIPEC in October 2016; capecitabine + bevacizumab in August 2017; Phase I clinical trial March-June 2018; was then enrolled in a Phase I clinical trial in October 2018 for Compound A and was administered Compound A at a dose of 360 mg. She had stable disease (-18%) at one of her six-week assessments. She also exhibited a biochemical response where her biomarkers CA 19-9 and CAE decreased rapidly following administration of Compound A and remained at low levels during the course of Compound A therapy (Figure 1). She tolerated the drug and continued its administration for more than 22 weeks.

NSCLC Tumor Responses: Patients with NSCLC KRAS G12C received daily dosages of 180 mg, 360 mg, 720 mg, or 960 mg, and 9 of 10 study patients had at least a stable disease response to therapy based on radiographic studies. carried out every six weeks, the results are shown in Fig. 2 with the estimated dose noted below each histogram. The duration and treatment of subjects in the NSCLC study are also shown in FIG. 3, where the top four columns correspond to patients receiving 960 mg of the total daily dose, the next six columns correspond to patients receiving 720 mg of the total daily dose; the next column corresponds to a patient receiving 360 mg of the total daily dose, and the bottom three columns correspond to patients receiving 180 mg of the total daily dose.

Responses of CRC and Other Solid Tumors: Patients with CRC or other solid tumor with G12C KRAS received a daily dose of 180 mg, 360 mg, 720 mg, or 960 mg, and the results of 17 of 19 study patients are shown in FIG. 4 (two did not show progression before week 6 and did not undergo the first six-week assessment). The results in Fig. 4 are based on radiographic examinations performed at each six-week assessment. The duration and treatment of subjects in the CRC/other study are also shown in FIG. 5, where the top two columns correspond to patients receiving 960 mg of the total daily dose, the next five columns correspond to patients receiving 720 mg of the total daily dose; the next eleven columns correspond to patients receiving 360 mg of the total daily dose, and the bottom three columns correspond to patients receiving 180 mg of the total daily dose.

Compound A Phase 1 Study Results: Thirty-five patients with G12C KRAS cancers (19 CRC, 14 NSCLC, 2 others - app) were enrolled in the Phase 1 study for Compound A. All had received 2 or more prior lines of therapy. No DLTs were recorded. Sixteen patients reported compound A-related adverse events, two reported grade 3 adverse events (anemia and diarrhea). The best tumor responses were tabulated, leaving 26 patients in the study. The results are shown in the table below. 3.

- 22 047200

Table 3

Treatment-related adverse event

Best tumor response in 29* patients Frequency Duration of response or stable disease** NSCLC (n=10) Partial answer 5 (2 confirmed) 7.3-27.4 weeks Stable disease 4 8.4-25.1 weeks Disease progression R" N/A CRC/other (n=19) Stable disease 14 7.3-24.0 weeks Disease progression 5# N/A *Six patients (4 NSCLC; 2 CRC/other) were unchanged from baseline based on radiographic examination at the data cutoff date (April 4, 2019). ^Response duration as of data cutoff date. All 5 patients with partial responses were still on treatment at the data cutoff date. ***Two of these patients (1 NSCLC; 1 CR) had early (<6 weeks) clinical progressive disease.

The pharmacokinetics of Compound A administered at a dose of 960 mg orally were as follows: Cmax, 7.84 μg/ml (SD, 8.09); AUC _{0-24 h} . - 140 h*mcg/ml (SD of 117); and t _1/2 ,z - 6.5 hours (SD of 4.2-8.0).

Updated results.

Updated results of this study were presented as a poster in Govindan, R., et. al., Phase 1 Study of AMG 510, a Novel KRAS ^G12C Inhibitor, in Advanced Solid Tumors With KRAS p. G12C Mutation at the European Society of Medical Oncology (ESMO) meeting September 27 - October 1, 2019 in Barcelona, Spain, the contents of which are hereby incorporated in their entirety. Additional results from this study will be presented in Fakih, MG, et al., CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRAS ^G12C , in patients with advanced colorectal cancer and Hong, DS, et al., CodeBreak 100: Phase 1 study of AMG 510, a novel KRAS ^G12C inhibitor, in patients with advanced solid tumors other than non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) at the meeting of the American Society of Clinical Oncology (ASCO) May 29-31 2020 (remotely), the contents of which are hereby incorporated in their entirety.

The study was also published as A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in subjects with a Specific KRAS Mutation (CodeBreak 100), Clinicaltrials.gov, Identifier No. NCT03600883, https://clinicaltrials. gov/ct2/show/NCT03600883 (last accessed May 3, 2020), the contents of which are hereby incorporated in their entirety.

The following data show that compound A demonstrated early promising antitumor activity in patients with advanced solid tumors harboring the p mutation. G12C KRAS, such as NSCLC, CRC and other tumor types.

The clinical trial design is summarized in the flowchart below.

| Phase 1, multi-site, open-label study - dose escalation |

Key Match

- Previous standard therapies received

or metastatic malignancy

- G12CKRAS mutation, as assessed by local molecular testing of tumor biopsies

- No active metastases in the brain

- 2-4 patients in each cohort

- Allowed individual dose escalation

- Additional patients may be added to any dose considered safe

Cohort 2 360 mg

Cohort 1

180 mg

Cohort 3 720 mg

Cohort 4,960 mg

- Daily repeated oral dosing in 21-day cycles

- Treatment until disease progression, intolerance or withdrawal of consent

- Radiographic examination every 6 weeks 'SB f

1L

I ^s

I ^s

Specific boost dose

Primary endpoints: dose-limiting toxicity (dCT). safety.

Key secondary endpoints: CR, objective response rate, duration of response, disease control rate, PFS, duration of stable disease

- 23 047200

^a 30 (+7) days after treatment for follow-up regarding safety assessment; every 12 weeks during long-term follow-up. PK: pharmacokinetics; PFS: progression-free survival.

Patients with non-small cell lung cancer (NSCLC).

The first patient was enrolled on August 27, 2018. By the data cutoff date of July 17, 2019, 76 patients were included, of which 34 with NSCLC (one with SCLC (this patient was recorded as SCLC (other tumor type category) at the time of cutoff data, and changed to NSCLC by participating study site after data cutoff).45 patients were included in the dose escalation cohort (total daily dose 180 mg (N=6), total daily dose 360 mg (N=13), total daily dose 720 mg (N=11), total daily dose 960 mg (N=15)) and the expansion cohort included 31 patients (total daily dose 960 mg (N=31)), resulting in 55 evaluable patients who completed the first 6 -week study or were characterized by early disease progression (PD). Of the 76 patients included, 52 remained on treatment and 24 discontinued due to PD (N=22) and death (N=2). was not caused by treatment-related adverse effects.

Table4

Initial characteristics

INITIAL CHARACTERISTICS N=76 MEDIAN AGE (RANGE) - YEARS 59.0 (33.0-78.0) WOMEN - N (%) 40 (52.6) PRIMARY TUMOR TYPE - N (%) NSCLC 34 (44.7) CRC 36 (47.4) SCLC ^a 1 (1.3) APPENDIX CANCER 3 (3.9) ENDOMETRIAL CANCER 1 (1.3) SMALL INTESTINE CANCER 1 (1.3) GENERAL CONDITION INDICATOR ON THE ECOG SCALE AT INITIAL LEVEL - N (%) 0 20 (26.3) 1 53 (69.7) 2 3 (3.9) PREVIOUS LINES OF SYSTEMIC ANTI-CANCER THERAPIES - N (%) 1 5 (6.6) 2 9(11.8) >2 62 (81.6) NUMBER OF TYPES OF THE PREVIOUS SYSTEM ANTI-CANCER THERAPY - MEDIAN (RANGE) 4.0(1-10)

- 24 047200 ^a This patient's tumor type was recorded as SCLC (other tumor types) at the time of data cutoff; however, the participating study center updated the tumor type to NSCLC after data collection ceased. CRC=colorectal cancer; ECOG=Eastern Cooperative Oncology Group; NSCLC=non-small cell lung cancer; SCLC=small cell lung cancer.

The following table shows the incidence of patient adverse events (AEs). No dose-limiting toxicity has been recorded. Additionally, no serious, treatment-related or fatal AEs were recorded. Most importantly, treatment-related AEs did not lead to treatment discontinuation. As a result, a total daily dose of Compound A of 960 mg was determined to be the booster dose and the recommended phase 2 dose.

Table 5

Summary of Adverse Event (AE) Frequency Data in Patients

ALL AE (N=76) - N (%) ALL AE RELATED TO TREATMENT (N=76) - N (%) ANY DEGREE 57 (75.0) 26 (34.2) DEGREE > 2 44 (57.9) 14(18.4) DEGREE > 3 24 (31.6) 6 (7.9) DEGREE > 4 8 (10.5) 0(0) DOSE-LIMITING TOXICITY 0(0) 0(0) SERIOUS AE 17 (22.4) 0 (0) ^s DEADLY AE 7 (9.2) ^A 0(0) AE LEADING TO DISCONTINUATION OF TREATMENT 2 (2.6) ⁱⁿ 0(0)

^a Seven patients had the following fatal AEs: dyspnea, aspiration, metastatic lung cancer, metastatic colorectal cancer, and vertebral compression fracture; none were treatment related.

^b Two patients with CRC discontinued treatment due to AE metastatic colorectal cancer.

^C One patient with NSCLC had a respiratory infection that was initially reported as a treatment-related serious AE in the summary; after a brief description, the research center confirmed that it was not related to treatment but was an underlying condition.

CRC=colorectal cancer; NSCLC=non-small cell lung cancer.

The incidence of treatment-related adverse reactions (AEs) in patients is detailed in the table below. Thus, 26 of 76 patients (34.2%) had treatment-related AEs, most of which were grade 1 or 2. 6 of 76 patients (7.9%) had 1 or more treatment-related adverse events. treatment, grade 3 (diarrhea or anemia). No treatment-related adverse events grade 4 or higher were observed.

Table 6

Frequency of treatment-related adverse events (AEs) in patients

ANY DEGREE (N=76) N (%) DEGREE 3 (N=76) N (%) ANY AE RELATED TO TREATMENT 26 (34.2) 6 (7.9) DIARRHEA I (14.5) 4 (5.3) NAUSEA 3 (3.9) 0(0) DRY MOUTH 2 (2.6) 0(0) ABDOMINAL PAIN 1 (1.3) 0(0) CHEILITIS 1 (1.3) 0(0) BURPING 1 (1.3) 0(0) FLATULENCE 1 (1.3) 0(0) VOMIT 1 (1.3) 0(0)

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INCREASED ALT LEVEL 2 (2.6) 0(0) INCREASED AST LEVEL 2 (2.6) 0(0) INCREASED ALKALINE LEVEL PHOSPHATASES IN THE BLOOD 2 (2.6) 0(0) ADVANCED LEVEL CREATINE PHOSPHOKINASES IN THE BLOOD 2 (2.6) 0(0) ALANINE AMINOTRANSFERASE 1 (1.3) 0(0) ASPARATE AMINE TRANSFERASE 1 (1.3) 0(0) REDUCED QUANTITY LYMPHOCYTES 1 (1.3) 0(0) REDUCED NUMBER OF WHITES BLOOD CELLS IN BLOOD 1 (1.3) 0(0) ANEMIA 3 (3.9) z (3.9) LEUKOPENIA 1 (1.3) 0(0) REDUCED APPETITE 2 (2.6) 0(0) HYPERKALEMIA 1(1,3) 0(0) HYPOKALEMIA 1 (1.3) 0(0) FATIGUE 2 (2.6) 0(0) DYSGEUSIA 1 (1.3) 0(0) PERIPHERAL NEUROPATHY 1 (1.3) 0(0) ARTHRALGIA 1 (1.3) 0(0) PROTEINURIA 1 (1.3) 0(0) NOSE BLEED 1 (1.3) 0(0) RASH 1 (1.3) 0(0) HEAT TIDE 1 (1.3) 0(0)

ALT=alanine aminotransferase; AST=aspartate aminotransferase.

The pharmacokinetic (PK) profile of Compound A (oral total daily dose 960 mg) at the PK data cutoff date of July 24, 2019 (N=32, including patients with NSCLC and CRC) was as follows (geometric mean; % coefficient of variation ( CV)): maximum serum concentration (Cmax) 7.50 µg/ml (98.3%), area under the pharmacokinetic curve (AUC) 65.3 h*µg/ml (81.7%) and half-life (t _1/2 ,z) 5.5 hours (1.8). Serum concentrations following administration remained for at least 22 hours above the 90% in vitro inhibitory concentration (IC ₉₀ ) in the 2-hour phosphorylated extracellular signal-regulated kinase (pERK) assay.

The best tumor response in patients with NSCLC at all dose levels and at the 960 mg dose is presented in the table below.

Table 7

Frequency of treatment-related adverse events (AEs) in patients

OUTCOMES EFFICIENCY PATIENTS ASSESSED (N=23) PATIENTS ASSESSED WHO RECEIVED 960 MG (N=13) BEST OVERALL ANSWER PR - N (%) 11 (48) 7(54) SD - N (%) 11 (48) 6(46) PD - N (%) 14) 0(0) OBJECTIVE RESPONSE FREQUENCY ^a 48% 54% DISEASE CONTROL RATE ¹³ 96% 100%

^a Response assessment is based on modified RECIST 1.1 criteria.

- 26 047200 ^b PR or SD per week 6.

PR: partial response; SD: stable disease; PD: disease progression. Patients Evaluated: Patients who completed the first 6-week study or had early PD.

The efficacy of Compound A in patients with NSCLC is shown in Figure 6 (% change from baseline in sum of largest diameters compared to evaluated NSCLC patients with available tumor data after baseline (N=22). It should be noted that patients presented in the rightmost column, those treated with a total daily dose of 960 mg had a complete response to the target lesion.

In fig. 7 shows the efficacy of Compound A in patients with NSCLC based on time to response and duration of treatment (NSCLC patients evaluated (N=23) versus treatment duration in weeks). 11 patients demonstrated a partial response (PR) with a median treatment duration of 15.1 weeks (range 4.1-42.3). Eight of these 11 patients continued to participate in the study. An additional 11 patients demonstrated stable disease (SD) with a median treatment duration of 10.0 weeks (range 4.1-35.1). Eight of these 11 patients continued to participate in the study.

In conclusion, Compound A showed early promising antitumor activity in patients with advanced solid tumors harboring the p.G12C KRAS mutation, such as NSCLC. In addition, Compound A was found to have a favorable safety profile at the dose levels tested, with no dose-limiting toxicity observed and no cumulative toxicity observed during long-term treatment.

Patients with colorectal cancer (CRC).

By the data cutoff date of January 8, 2020, 42 patients with CRC were included (cohort 1: 3 patients at a total daily dose of 180 mg, cohort 2: 10 patients at a total daily dose of 360 mg, cohort 3: 4 patients at a total daily dose 720 mg, cohort 4: 25 patients for a total daily dose of 960 mg). The median follow-up period was 7.9 months (range: 4.2-15.9 months). Eight patients continued treatment. Thirty-four patients discontinued due to disease progression (32) and patient requests (2). All included patients had received previous lines of systemic anticancer therapy. 45% of patients received more than 3 lines of therapy.

Table 8

Initial characteristics

INITIAL CHARACTERISTICS N=42 MEDIAN AGE (RANGE) - YEARS 57.5 (33-82) WOMEN - N (%) 21(50) INDICATOR OF GENERAL CONDITION ACCORDING TO THE ECOGHA SCALE AT INITIAL LEVEL - N (%) 0 17(40.5) 1 25 (59.5) PREVIOUS LINES OF SYSTEMIC ANTI-CANCER THERAPIES - N (%) 1 2 (4.8) 2 11 (26.2) 3 10 (23.8) >3 19 (45.2) NUMBER OF TYPES OF THE PREVIOUS SYSTEM ANTI-CANCER THERAPY - MEDIAN (RANGE) 3 (1-4)

ECOG=Eastern Cooperative Oncology Group.

The following two tables show the incidence of patient adverse events (AEs). 20 of 42 patients had treatment-related AEs, most of which were grade 2 or lower. Diarrhea and anemia were recorded as treatment-related grade 3 AEs occurring in 1 patient each. No dose-limiting toxicity was observed. As discussed above, 960 mg of the total daily dose of Compound A was determined as the booster dose and the recommended phase 2 dose.

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Table 9

Summary of Adverse Event (AE) Frequency Data in Patients

TREATMENT EMERGENT AE (TEAE), N=42, N (%) TEAE RELATED WITH TREATMENT N=42,N(%) ANY DEGREE 38 (90.5) 20 (47.6) DEGREE > 2 29 (69.0) 9 (21.4) DEGREE > 3 13 (31.0) 2 (4.8) DEGREE > 4 3 (7.1) 0 (0.0) VALUES DOSE-LIMITING TOXICITY 0 (0.0) o (0,0) SERIOUS AE 10 (23.8) o (0,0) DEADLY AE z (7.1) o (0,0) AE LEADING TO TERMINATION TREATMENTS 2 (4.8) 0 (0.0)

AE: adverse event.

Table 10

Treatment-emergent TEAEs, any grade, occurring in >1 patient

TREATMENT-ASSOCIATED TEAE, ANY GRADE, ARISING IN > 1 PATIENT N=42,N(%) DIARRHEA 8 (19.0) FATIGUE 4 (9.5) NAUSEA 2 (4.8) ADVANCED LEVEL CREATINE PHOSPHOKINASES IN THE BLOOD 2 (4.8) ANEMIA 2 (4.8) VOMIT 2 (4.8)

Tumor response in patients with CRC at all dose levels and at a total daily dose of 960 mg is presented in the table below. In terms of efficacy, a confirmed partial response was observed in 3 patients, all of whom received the 960 mg dose. Responses were longitudinal and were still ongoing at the cutoff date for data collection. Additionally, 29 patients had stable disease, resulting in a disease control rate of 76.2%.

- 28 047200

Table 11

Tumor response

TUMOR RESPONSE ALL LEVELS DOSE N=42, N (%) TOTAL DAILY DOSE 960 MG N=25.N(%) BEST OVERALL ANSWER CONFIRMED PARTIAL ANSWER - N (%) STABLE DISEASE - N (%) DISEASE PROGRESSION - N (%) NOT COMPLETED - N (%) ^A h (7.1) 29 (69.0) 9(21.4) 1 (2.4) 3 (12.0) 17 (68.0) 4(16.0) 1 (4.0) OBJECTIVE RESPONSE RATE - % (95% ST) 7.1 (1.50, 19.48) 12.0 (2.55.31.22) DISEASE CONTROL FREQUENCY - % (95% ST) 76.2 (60.55, 87.95) 80.0 (59.30, 93.17) DURATION OF RESPONSE FOR 3 PATIENTS - MONTHS 1.4+, 4.2+, 4.3+ 1.4+, 4.2+, 4.3+ DURATION STABLE ILLNESS - MONTHS MEDIAN (MIN, MAX) 4.2 (2.5+, 11.0) 4.2 (2.6, 5.7+)

^a The patient had disease progression and no post-baseline measurements were available.

+: censored indicator.

Progression-free survival (PFS) is shown in Fig. 8. Progression-free survival at all dose levels was 4.0 months (median (min, max): 0.7, 11.0) and at 960 mg - 4.2 months (median (min, max): : 1.2, 5.7+; +: censored indicator). The 3-month and 6-month PFS rates for all doses were 58.5% and 20.6%, respectively. The 3-month PFS rate for a total daily dose of 960 mg was 59.7%. Overall survival (OS) is shown in Figure 9. Overall survival at all dose levels was 10.1 months (median (min, max): 1.3+, 11.4+; +: censored; NR: not reached )) and at 960 mg NE (2.3, 8.0+). The 6-month OS rate was 76.4% for all doses and 82.9% for the total daily dose of 960 mg.

The effectiveness of Compound A in patients with CRC is shown in FIG. 10 (% change from baseline in sum of largest diameters compared to evaluated CRC patients with tumor data available after baseline (N=39). Three patients were not included in the graph in Figure 10 due to missing data on tumors after baseline (1 PD, 1 SD, 1 not completed due to clinical progression).

In fig. 11-15 show the change in tumor weight from baseline over time for patients with CRC with the introduction of all four dosages of the compound (Fig. 11: total daily dose of 180 mg, 360 mg, 720 mg and 960 mg) and for individual dosages (Fig. 12 -15).

In fig. 16 and 17 show time to response and treatment over time for patients with CRC dosed with Compound A at various doses.

In conclusion, three of 42 patients (7.1%) previously treated with high-dose metastatic CRC with the p.G12C KRAS mutation had durable partial responses to Compound A. In addition to the 3 patients, 29 patients achieved disease control. resulting in a disease control rate of 76.2% and a median progression-free survival (PFS) of 4.0 months (range: 0.7-11.0). Additionally, Compound A was well tolerated with mild treatment-related toxicity in patients with CRC, consistent with previous results.

Patients with advanced solid tumors other than NSCLC and CRC.

By the data cutoff date of January 8, 2020, 25 patients with the following tumor types were included: pancreatic cancer (10 patients), appendix cancer (4 patients), endometrial cancer (2 patients), cancer of unknown primary site (2 patients), bile duct cancer (1 patient), sinonasal cancer (1 patient), ampullary colon cancer (1 patient), small bowel cancer

- 29 047200 colon (1 patient), melanoma (1 patient), small cell lung cancer (1 patient) and esophageal cancer (1 patient). 2 patients with appendiceal cancer received total daily doses of Compound A of 360 and 720 mg, respectively. The remaining 23 patients received a total daily dose of Compound A of 960 mg. Median follow-up was 4.3 months (range: 0.1-12.6 months). 22 patients were followed for >7 weeks and assessed for response. By the data cutoff date, 12 patients had discontinued treatment with disease progression as the most common reason. All included patients had received previous lines of systemic anticancer therapy, and 84% of included patients had received more than 1 previous line.

Table 12

Initial characteristics

INITIAL CHARACTERISTICS N=25 MEDIAN AGE (RANGE) - YEARS 60.0 (40-75) WOMEN - N (%) 9 (36.0) GENERAL CONDITION INDICATOR ON THE ECOG SCALE AT INITIAL LEVEL - N (%) 0 7 (28.0) 1 14 (56.0) 2 4(16.0) PREVIOUS LINES OF SYSTEMIC ANTI-CANCER THERAPIES - N (%) 1 4(16.0) 2 5 (20.0) 3 6 (24.0) >3 9 (36.0) ABSENCE 1 (4.0) NUMBER OF TYPES OF THE PREVIOUS SYSTEM ANTI-CANCER THERAPY - MEDIAN (RANGE) 3 (1-4)

ECOG=Eastern Cooperative Oncology Group.

The following table shows the incidence of patient adverse events (AEs). Treatment-related TEAEs recorded for more than one patient were diarrhea (2 of 25 patients) and fatigue (2 of 25 patients). Treatment-associated grade 3 TEAEs reported for more than one patient were diarrhea (1 of 25 patients) and pneumonia (1 of 25 patients). No dose-limiting toxicity or treatment-related adverse events leading to treatment discontinuation were observed. As discussed above, 960 mg of the total daily dose of Compound A was determined to be the booster dose and the recommended phase 2 dose.

Table 13

Summary of Adverse Event (AE) Frequency Data in Patients

ALL AE ARISING OUT DURING TREATMENT (TEAE), N=25,N(%) ALL AE RELATED TO TREATMENT N=25,N(%) ANY DEGREE 20 (80.0) 9 (36.0) DEGREE > 2 17 (68.0) 4 (16.0) DEGREE > 3 15 (60.0) 2 (8.0) DEGREE > 4 4 (16.0) 0 (0.0) VALUES DOSE-LIMITING TOXICITY 0 (0.0) o (0,0) SERIOUS AE 13 (52.0) 1 (4.0) DEADLY AE 4 (16.0) 0 (0.0) AE LEADING TO TERMINATION TREATMENTS 3 (12.0) o (0,0)

- 30 047200

AE: adverse event.

Tumor response in these patients is presented in the table below. 22 patients were assessed for tumor response. 3 had a confirmed partial response, 13 had stable disease, and 6 had disease progression. The 3 partial responders had appendiceal cancer, melanoma, and endometrial cancer, respectively. The 13 patients with stable disease included 6 with pancreatic cancer, 2 with appendix cancer, 1 with colon ampullary cancer, 1 with bile duct cancer, 1 with endometrial cancer, 1 with sinonasal cancer, and 1 with unknown primary location. The 3 patients with pancreatic cancer who achieved stable disease had a reduction close to 30% according to RECIST 1.1.

Table 14

Tumor response

BEST TUMOR RESPONSE PATIENTS ASSESSED, N=22 CONFIRMED PARTIAL ANSWER - N TYPES OF TUMOR (N) 3 APPENDIX (1) MELANOMA (1) ENDOMETRIA (1) STABLE DISEASE - N TYPES OF TUMOR (N) 13 PANCREAS (6) APPENDIX (2) AMPULARY DEPARTMENT OF TOLSTAYA GUTS (1) BALL DUCT (1) ENDOMETRIA (1) SINONASAL CANCER (1) UNKNOWN PRIMARY LOCALIZATIONS (1) PROGRESSION DISEASES - N TYPES OF TUMOR (N) 6 PANCREAS (2) APPENDIX (1) SMALL CELL LUNG CANCER (1) ESOPHAGUS (1) SMALL INTESTINE CANCER (1)

The efficacy of Compound A in these patients is shown in Figure 18 (% change from baseline in sum of largest diameters compared to evaluable patients with available tumor data after baseline (N=19). Three patients were not included in the plot in Figure 18 due to missing tumor data after baseline (2 patients having appendiceal cancer (1 PD, 1 SD) and one patient having pancreatic cancer (PD).

In fig. Figure 19 shows time to response and treatment over time for these patients.

In conclusion, encouraging anticancer activity was observed in many tumor types with G12C KRAS. Confirmed partial responses were observed in 3 patients with appendiceal cancer, melanoma and endometrial cancer, respectively. 6 of 8 patients with pancreatic cancer evaluated achieved stable disease, with three of them having a 30% reduction in tumor burden. Toxicity associated with Compound A was mild and well manageable, consistent with previous results.

Although the present invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions or additions of procedures and protocols can be made without departing from the spirit and scope of the present invention. inventions. Accordingly, it is intended that the present invention be defined by the scope of the following claims and that such claims are to be interpreted as broadly as is practical.

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Claims (31)

CLAIM 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound, wherein the compound is or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a total daily amount corresponding to 960 mg of the compound. 2. The method of claim 1, wherein the cancer is non-small cell lung cancer, small intestinal cancer, appendix cancer, colorectal cancer, endometrial cancer, pancreatic cancer, skin cancer, gastric cancer, nasal cancer or bile duct cancer. 3. The method of claim 1, wherein the cancer is non-small cell lung cancer. 4. The method of claim 1, wherein the cancer is locally advanced or metastatic non-small cell lung cancer. 5. The method according to claim 1, wherein the cancer is colorectal cancer. 6. The method according to claim 1, wherein the cancer is pancreatic cancer. 7. Method according to any one of paragraphs. 1-6, wherein the cancer is a cancer with the G12C KRAS mutation. 8. Method according to any one of paragraphs. 1-7, wherein the subject, prior to initiating therapy with the compound, has been exposed to at least one other systemic cancer therapy. 9. Method according to any one of paragraphs. 1-8, wherein the subject, prior to initiation of therapy with the compound, has been exposed to at least two other systemic cancer therapies. 10. Method according to any one of claims 1 to 9, wherein the compound is administered orally. 11. Method according to any one of claims 1 to 10, wherein the compound is administered as a single daily dose. 12. Method according to any one of claims 1 to 11, wherein the compound is administered in the form of a tablet. 13. The method of any one of claims 1 to 12, wherein the method further comprises administering a chemotherapy drug to the subject. 14. The method of claim 13, wherein the chemotherapy drug contains an anti-PD1 antibody. 15. The method of claim 14, wherein the anti-PD1 antibody is pembrolizumab, nivolumab or AMG 404. 16. The method of claim 15, wherein the anti-PD1 antibody is pembrolizumab. 17. The method of claim 15, wherein the anti-PD1 antibody is AMG 404. 18. The method of claim 13, wherein the chemotherapy drug contains an anti-PDL1 antibody. 19. The method of claim 18, wherein the anti-PDL1 antibody is atezolizumab, avelumab or durvalumab. 20. The method of claim 19, wherein the anti-PDL1 antibody is atezolizumab. 21. The method of claim 13, wherein the chemotherapy drug contains a MEK inhibitor. 22. The method of claim 21, wherein the MEK inhibitor is trametinib, pimasertib, PD-325901, MEK162, TAK-733, GDC-0973, or AZD8330. 23. The method of claim 22, wherein the MEK inhibitor is trametinib. 24. The method of claim 13, wherein the chemotherapy drug contains a CDK4/6 inhibitor. 25. The method of claim 24, wherein the CDK4/6 inhibitor is abemaciclib or palbociclib. 26. The method of claim 25, wherein the CDK4/6 inhibitor is palbociclib. 27. The method of claim 13, wherein the chemotherapy drug contains a PI3K inhibitor. 28. The method of claim 27, wherein the PI3K inhibitor is AMG 511 or buparlisib. 29. The method according to claim 13, where the chemotherapy drug contains carboplatin. 30. The method according to claim 13, where the chemotherapy drug contains pemetrexed. 31. Method according to any one of claims 1 to 30, wherein the compound is administered in the form of a free base. -